Surfing the Protein-Protein Interaction Surface Using Docking Methods: Application to the Design of PPI Inhibitors

Abstract

Blocking protein-protein interactions (PPI) using small molecules or peptides modulates biochemical pathways and has therapeutic significance. PPI inhibition for designing drug-like molecules is a new area that has been explored extensively during the last decade. Considering the number of available PPI inhibitor databases and the limited number of 3D structures available for proteins, docking and scoring methods play a major role in designing PPI inhibitors as well as stabilizers. Docking methods are used in the design of PPI inhibitors at several stages of finding a lead compound, including modeling the protein complex, screening for hot spots on the protein-protein interaction interface and screening small molecules or peptides that bind to the PPI interface. There are three major challenges to the use of docking on the relatively flat surfaces of PPI. In this review we will provide some examples of the use of docking in PPI inhibitor design as well as its limitations. The combination of experimental and docking methods with improved scoring function has thus far resulted in few success stories of PPI inhibitors for therapeutic purposes. Docking algorithms used for PPI are in the early stages, however, and as more data are available docking will become a highly promising area in the design of PPI inhibitors or stabilizers.

Keywords: docking; drug-like molecules; hot spots; protein docking; protein-protein interactions; virtual screening.

Figure 1

A schematic diagram for the design of PPI inhibitors and docking methods used at different stages of the design.

Figure 2

Crystal structure of complex of AMA1-RON2 peptide (PDB ID:3ZWZ). AMA1 is shown as the surface and RON2 is shown in magenta. Amino acids from AMA1 that are critical for binding are labeled with three-letter codes. Amino acids from RON2 that are critical for binding and used in the design of the pharmacophore model are shown as sticks (magenta) and labeled with single letter codes for amino acids. Four point pharmacophore (shown with circles) was generated based on the PPI interaction. However, Tyr251 was in the exclusion sphere in the pharmacophore generated [204]. PyMol (Schrodinger LLC, Portland, OR, USA) was used to generate the figure based on the information from Pihan et al. [204].

Figure 3

(A) Crystal structure of the complex of VWF-A1 and GPIbα (PDB ID: 1SQ0) [209] showing the hot spots determined by computational methods. Residues in the hot spot region of VWF-A1 are shown as red sticks. Residues from the hot spots of GPIbα are shown as sticks in magenta. Amino acids from VWF-A1 are labeled with three-letter codes and those from GPIbα are labeled with single-letter codes; (B) Crystal structure of the complex of VWF-A1 and GPIbα (PDB ID: 1SQ0) [209] overlapped with the unbound structure of GPIbα (PDB ID: 1P9A) (shown in black). Note the marked oval shape where there is a change in the conformation between the free and bound states of GPIbα. This region is the most probable hot spot on the protein to be involved in binding of a PPI inhibitor [206]. PyMol (Schrodinger LLC) was used to generate the figure based on the information from Broos et al. [206].

Figure 3

(A) Crystal structure of the complex of VWF-A1 and GPIbα (PDB ID: 1SQ0) [209] showing the hot spots determined by computational methods. Residues in the hot spot region of VWF-A1 are shown as red sticks. Residues from the hot spots of GPIbα are shown as sticks in magenta. Amino acids from VWF-A1 are labeled with three-letter codes and those from GPIbα are labeled with single-letter codes; (B) Crystal structure of the complex of VWF-A1 and GPIbα (PDB ID: 1SQ0) [209] overlapped with the unbound structure of GPIbα (PDB ID: 1P9A) (shown in black). Note the marked oval shape where there is a change in the conformation between the free and bound states of GPIbα. This region is the most probable hot spot on the protein to be involved in binding of a PPI inhibitor [206]. PyMol (Schrodinger LLC) was used to generate the figure based on the information from Broos et al. [206].

Figure 4

(A) Crystal structure of the complex of CD2 and CD58 (PDB ID: 1QA9) [217] adhesion domain involved in the recognition of T cells and antigen-presenting cells. Salt bridges and hydrogen bonds are shown by dashed lines. The hydrophobic hot spot is shown as magenta colored sticks. Note that, although the PPI surface is dominated with salt bridges and hydrogen bonds, the hydrophobic interaction between Tyr86, Phe46, and the Lys34 side chain sandwiched between the aromatic residues forms the hot spot; (B) A cluster of low-energy docked structures of a peptide bound to the CD58 protein adhesion domain [218,219,220]. PyMol (Schrodinger LLC) was used to generate the figure.

Figure 5

Crystal structure of the HER2 protein (PDB ID: 3N85) [233] extracellular domain IV shown in surface representation. (A) Hot-spot region on the surface was identified by FTMAP [150]. Two hot spots were identified; (B) Docking of a peptidomimetic designed to bind to domain IV of HER2 protein. The peptidomimetic docked at rank 1 hot spot suggests that hot spots are suitable sites for the design of PPI inhibitors [231]. PyMol (Schrodinger LLC) was used to generate the figure.

Figure 5

Crystal structure of the HER2 protein (PDB ID: 3N85) [233] extracellular domain IV shown in surface representation. (A) Hot-spot region on the surface was identified by FTMAP [150]. Two hot spots were identified; (B) Docking of a peptidomimetic designed to bind to domain IV of HER2 protein. The peptidomimetic docked at rank 1 hot spot suggests that hot spots are suitable sites for the design of PPI inhibitors [231]. PyMol (Schrodinger LLC) was used to generate the figure.

Figure 6

Crystal structure of HIV-1 nef-SH3 domain (PDB ID:1AVZ). Nef is shown in surface representation and SH3 domain in magenta. Note the interaction of SH3 domain with hydrophobic grove that is called RT loop binding region. Residues surround the groove are shown in dark shade. Compounds were screened based on RTloop binding region [235]. PyMol (Schrodinger LLC) was used to generate the figure based on the information from Betzi et al. [235]. Permission obtained. Copyright (2007) National Academy of Sciences, U.S.A.